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Kormann, M.S.* ; Hector, A.* ; Marcos, V.* ; Mays, L.E.* ; Kappler, M.* ; Illig, T. ; Klopp, N. ; Zeilinger, S. ; Carevic, M.* ; Rieber, N.* ; Eickmeier, O.* ; Zielen, S.* ; Gaggar, A.* ; Moepps, B.* ; Griese, M.* ; Hartl, D.*

CXCR1 and CXCR2 haplotypes synergistically modulate cystic fibrosis lung disease.

Eur. Respir. J. 39, 1385-1390 (2012)
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Cystic fibrosis (CF) lung disease severity is largely independent on the CF transmembrane conductance regulator (CFTR) genotype, indicating the contribution of genetic modifiers. The chemokine receptors CXCR1 and CXCR2 have been found to play essential roles in the pathogenesis of CF lung disease. Here, we determine whether genetic variation of CXCR1 and CXCR2 influences CF lung disease severity. Genomic DNA of CF patients in Germany (n=442) was analysed for common variations in CXCR1 and CXCR2 using a single-nucleotide polymorphism (SNP) tagging approach. Associations of CXCR1 and CXCR2 SNPs and haplotypes with CF lung disease severity, CXCR1 and CXCR2 expression, and neutrophil effector functions were assessed. Four SNPs in CXCR1 and three in CXCR2 strongly correlated with age-adjusted lung function in CF patients. SNPs comprising haplotypes CXCR1_Ha and CXCR2_Ha were in high linkage disequilibrium and patients heterozygous for the CXCR1-2 haplotype cluster (CXCR1-2_Ha) had lower lung function compared with patients with homozygous wild-type alleles (forced expiratory volume in 1 s ≤70% predicted, OR 7.24; p=2.30×10(-5)). CF patients carrying CXCR1-2_Ha showed decreased CXCR1 combined with increased CXCR2 mRNA and protein expression, and displayed disturbed antibacterial effector functions. CXCR1 and CXCR2 genotypes modulate lung function and antibacterial host defence in CF lung disease.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Chemokines; cystic fibrosis; G-protein coupled receptor; lung function; polymorphism; MANNOSE-BINDING LECTIN; SEVERITY; ASSOCIATION; NEUTROPHILS; POPULATION; EXPRESSION; POLYMORPHISMS; MODIFIERS
Sprache
Veröffentlichungsjahr 2012
HGF-Berichtsjahr 2012
ISSN (print) / ISBN 0903-1936
e-ISSN 1399-3003
Zeitschrift European Respiratory Journal
Quellenangaben Band: 39, Heft: 6, Seiten: 1385-1390 Artikelnummer: , Supplement: ,
Verlag European Respiratory Society
Verlagsort Sheffield
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Molecular Epidemiology (AME)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504200-001
PubMed ID 22088968
DOI 10.1183/09031936.00130011
WOS ID WOS:000305369900017
Scopus ID 84861854607
Erfassungsdatum 2012-06-19
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